This application proposes expanded programs of patient-oriented research and mentoring by Laura J. Balcer, M.D., M.S.C.E., an established clinical investigator whose work has focused on the development of visual outcomes for clinical trials in multiple sclerosis (MS). Dr. Balcer's research has demonstrated validity for low-contrast letter acuity and for retinal nerve fiber layer (RNFL) thickness and macular volume by optical coherence tomography (OCT) in MS, but has not established roles for these parameters in outcomes assessment for acute optic neuritis (ON), a model for acute demyelization and axonal/neuronal loss in MS and an ideal target for examining neuroprotective therapies. The research plan will accomplish the following aims: Specific Aim 1: Refine and validate low-contrast letter acuity and OCT as new visual outcomes for clinical trials in MS, and in acute ON as a model system for future testing of neuroprotective agents. Specific Aim 2: Determine how new visual outcomes, low-contrast letter acuity and OCT, reflect vision-specific and overall health-related quality of life in longitudinal studies of MS and ON, and examine the validity and usefulness of a new 10-ltem Neuro-Ophthalmic Supplement to the 25-ltem NEI Visual Functioning Questionnaire (NEI-VFQ-25) in these patient populations. These investigations will further define potential roles for new measures of low-contrast letter acuity and OCT in MS clinical trials, and will apply paradigms from MS vision research to the study of acute ON as a more specific model system for assessment of natural history and neuroprotective treatment trial outcomes. Participation by mentees in refinement of study design, performance of hands-on testing, data analysis, and manuscript preparation will be a central focus of the candidate's mentoring plan. These proposed new projects have been designed and selected to facilitate trainee involvement, and are sufficiently flexible and varied in scope to incorporate mentees in Neurology at all levels of training. Public Health Statement: MS and optic neuritis are leading causes of visual loss among young and middle-aged adults in the U.S. This work will provide support for additional research and for mentoring of beginning clinician scientists in the development of improved testing methods for vision in these conditions.